Project Summary/Abstract The experiments of this proposal address a novel approach towards vaccination against HIV disease, namely: to create a vaccine that will prevent, rather than to elicit, a robust immune response against the virus. The rationale for this approach is prompted by several observations: there is no clear evidence that a robust immune response will be protective; HIV replication and spread are fostered, not hindered, by pro-viral effects associated with immune activation and inflammation; virus replication that occurs in the absence of persistent immune response does not cause disease; and perhaps most tellingly, a vaccine designed to induce strong adaptive responses against HIV was recently found to result in higher, not lower, rates of infection compared to placebo. These observations prompt an alternative, if counterintuitive, hypothesis: the best response to HIV might be no response at all, i.e., an effective vaccine should induce tolerance to HIV instead. Tolerance to HIV may result in abortive infection because, absent the effects of inflammation that normally drive viral replication and spread (e.g., the pro-viral impact of certain cytokines and of enhanced rates of cell proliferation and migration), infected cells may simply be cleared. This possibility is especially compelling when considering mother-to-child transmission of HIV. Thus, we have recently shown that maternal cells (and, presumably, HIV) can readily cross the placenta into the fetus; yet, very few babies born to HIV-infected mothers are infected in utero. The experiments of this proposal test the hypothesis that exposure of the fetus to HIV in utero will induce a tolerogenic response that is protective. To test this hypothesis, a multidisciplinary team has been assembled to evaluate tolerance induction in the context of the SIV-infected rhesus macaque, a well-developed model with unique similarities to human placentation and HIV infection. Our specific aim is to demonstrate that in utero exposure of the fetal rhesus macaque to SIV will induce a tolerogenic immune response that will protect against pathogenic SIV infection after birth. We will directly examine whether SIV can cross the placenta from the infected mother into the fetus and evaluate the immune response made by the fetus against SIV. We will also use a prototype vaccine to inoculate the fetus directly in utero, to determine whether a tolerogenic immune response can then be made. Finally, we will determine whether such exposure of the fetus to SIV will lead to a protective response against infection by SIV after birth. Within a four-year period of time, we should be in a position to definitively state whether or not this approach holds promise.